LLM ADVANCES IN LLM Current Developments in the Management of Leukemia, Lymphoma, and Myeloma Section Editor: Susan O’Brien, MD Update on Proteasome Inhibitors in Multiple Myeloma Paul G. Richardson, MD R.J. Corman Professor of Medicine Harvard Medical School Director of Clinical Research Clinical Program Leader Jerome Lipper Multiple Myeloma Center Division of Hematologic Malignancy Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts H&O Which proteasome inhibitors are available agents ixazomib, oprozomib, and marizomib. Ixazomib in or in development? particular shows great promise, especially in combination with lenalidomide and dexamethasone; it is now in several PGR The number of proteasome inhibitors is expanding. phase 3 trials. The first agent in this class was bortezomib (Velcade, Mil- lennium Pharmaceuticals), which received approval from H&O What are some of the important the US Food and Drug Administration (FDA) for use in differences between these agents? multiple myeloma as a third-line treatment in 2003, second- line treatment in 2005, and first-line treatment in 2008. The PGR One obvious difference is that ixazomib and agent was also approved for use as a second-line treatment oprozomib are oral agents, whereas bortezomib and carfil- in mantle cell lymphoma in 2006. In 2012, subcutaneous zomib are administered either subcutaneously or intrave- administration was approved for all approved indications. nously. Furthermore, proteasome inhibitors in clinical use The next proteasome inhibitor to receive approval was encompass a broad scope of drugs that have important carfilzomib (Kyprolis, Onyx), in 2012. This was the first mechanistic differences. Specifically, bortezomib and ixa- of the second-generation agents, which was an exciting zomib are peptide boronates, carfilzomib and oprozomib advance. Carfilzomib had increased potency compared are epoxyketones, and marizomib is a b-lactone. with bortezomib and irreversible binding on the target. Peptide boronates work by reversibly targeting the In addition, preclinical data suggested that carfilzomib b subunits of the proteasomal apparatus, and inhibit might be active in the face of bortezomib resistance. the proteasome as a result. Epoxyketones, by contrast, Carfilzomib was awarded accelerated approval for patients irreversibly inhibit the proteasome by covalently bind- with multiple myeloma whose disease has progressed after ing to the b subunits—as does the b-lactone marizomib. receiving at least 2 prior therapies, including bortezomib Interestingly, while carfilzomib binds both b-1 and b-2 and an immunomodulatory agent. Contingent on the subunits, marizomib appears to bind all 3 b subunits results of recently completed phase 3 combination trials, and has the most potency and the broadest effect in vitro carfilzomib is likely to obtain full approval soon. to date. In this context, we rely on the regeneration of In addition, several proteasome inhibitors are being the proteasome in both epoxyketones and b-lactones to studied that hopefully will receive FDA approval over restore normal tissue activity, and so hope to exploit a the next few years. These include the orally bioavailable therapeutic index accordingly. Clinical Advances in Hematology & Oncology Volume 12, Issue 3 March 2014 179 LLM H&O Could you talk about the advantages and treatment. Single-agent studies have been encouraging, disadvantages of these agents? with responses seen in patients with highly resistant and advanced disease. Side effects have included fatigue, PGR Bortezomib has a well understood and manageable thrombocytopenia, and transient central nervous system safety profile, especially when administered subcutane- toxicity characterized by mild confusion and occasional ously. It is rarely associated with significant adverse cardiac headache. As with carfilzomib, caution is needed in or pulmonary side effects, and it is a very good choice patients with renal dysfunction, and peripheral neuropa- for multiple myeloma patients with kidney dysfunction. thy is very uncommon. Importantly, there has been no However, a common side effect of bortezomib is neuropa- significant cardiac toxicity to date. thy, which can be dose limiting. Although we have become much better at managing this side effect, an important H&O How has the role of proteasome inhibitors improvement as mentioned earlier was the introduction evolved in multiple myeloma? of subcutaneous administration in 2012. Subcutaneous administration has been shown to work just as well and PGR The uses for these agents have dramatically expanded, cause less neuronal injury compared with intravenous use, with their role as “backbone” agents truly validated in which of course can still be used if preferred. numerous trials. The ability to be selective for both resistance In terms of other peptide boronates, ixazomib has and tolerability, in addition to now having the convenience a more rapid-on/rapid-off pharmacology that makes it of oral administration, represents remarkable progress for more specific than bortezomib to tumor cells. As a result, this drug class as a whole. ixazomib has a potentially improved therapeutic index. The drug does cause skin rash, which is generally man- H&O Could you talk about your studies with ageable, but it has only mild to moderate gastrointestinal ixazomib? toxicity. In fact, the favorable tolerability profile of ixazo- mib makes it an ideal drug to use for maintenance treat- PGR In 2012, my colleague Dr Shaji Kumar presented ment as well as in combination treatment. Of course, it on our behalf the results of our phase 1/2 trial with also has the advantage of being an oral medication rather weekly ixazomib citrate (MLN9708) in combination than an injectable one. Large trials with lenalidomide and with lenalidomide and dexamethasone at the Ameri- dexamethasone are now under way in various settings, can Society of Hematology (ASH) meeting. (Ixazomib as described previously. The fact that all-oral regimens citrate hydrolyzes to ixazomib [MLN2238], the biologi- are being tested that combine proteasome inhibitors cally active form of the drug.) This study included 65 with immunomodulatory compounds makes these truly patients with previously untreated multiple myeloma landmark studies. who received 3 weekly doses of ixazomib citrate per 28 The big advantage of carfilzomib (as an irreversible days in combination with lenalidomide (Revlimid, Cel- epoxyketone proteasome inhibitor) over the boronate gene) and dexamethasone, for up to 12 cycles. Patients peptide class is that it appears to be more potent. Of par- also received maintenance therapy with monthly ixazo- ticular note, carfilzomib only rarely produces neuropathy. mib citrate until the disease progressed. Patients could Side effects of carfilzomib also include cardiac, pulmo- discontinue treatment for autologous stem cell trans- nary, and renal effects, which are uncommon, along with plant after six 28-day cycles. fatigue and thrombocytopenia, which are more common. Side effects included fatigue, rash, nausea, and vom- Generally speaking, however, carfilzomib is well tolerated, iting, all of which proved generally manageable with sup- and it can be effective when bortezomib has failed. portive care and dose reduction. Oprozomib is similar to carfilzomib, but like ixazo- After a median follow-up of approximately 4 mib it can be given in oral form, which also makes it a months, the overall response rate was 88%, including very very exciting option with considerable potential. One dis- good partial responses in 40% of patients and complete advantage is that it causes significant gut toxicity, which responses in 18%. Of the 50 patients who received at least can be dose limiting, as well as other side effects, includ- 4 cycles of therapy, the overall response rate was encourag- ing fatigue and low platelet counts, which are generally ing at 96%, with very good partial responses in 44% of manageable with supportive care. Nonetheless, we await patients and complete responses in 26%. future studies of this agent with great interest. At the most recent ASH meeting in December of last Marizomib, a b-lactone, has the advantage of being year, we presented our phase 1/2 results with twice-weekly the most potent agent studied so far. Like carfilzomib, oral ixazomib citrate in combination with lenalidomide and marizomib can overcome bortezomib resistance and dexamethasone in patients with newly diagnosed multiple is especially active preclinically as part of combination myeloma. This study included 64 patients, with transplant- 180 Clinical Advances in Hematology & Oncology Volume 12, Issue 3 March 2014 LLM eligible patients being able to discontinue treatment for H&O Is there anything you would like to add about autologous stem cell transplant after 8 or more cycles. proteasome inhibitors, and in particular ixazomib? The majority of patients—77%— received 8 or more cycles, and 20% received 16 or more cycles. The discon- PGR It is very exciting to now have all-oral regimens tinuation rate was relatively low, at 14%. that can be given as initial treatment and to see such a Among the 58 patients who were evaluable for high quality of responses. Moreover, we are seeing both response, 93% had a partial response or better and 67% favorable tolerability and durable clinical benefit with the had a very good partial response or better, including a second-generation agents. 24% complete response rate and a 14% stringent com- Specifically, I think ixazomib